Vlife Mds new software for mol.designing

 

VLifeMDS™ (Molecular Design Suite), is a Medicinal Chemist’s workbench for computer aided drug design (CADD) and molecule discovery. VLifeMDS is completely scalable and customizable to address the variegated problems in molecular design and prediction of new molecules. Learn more about VLifeMDS™ Suite VLifeMDS™ Suite Tools Available Plug-ins Vlife Engine™ BioPredicta™ GQSAR™ ChemDBS™ LeadGrow™ Chemstere QSARPlus™ Molsign™ Tautomer ProViz™ Back to Overview

VLife BioPredicta™ Features Homology Modeling Protein Analysis Protein Handling Molecular Docking

BioPredicta module allows to perform all biomolecule related activities, such as homology modeling, protein analysis and to study protein - ligand interactions. In order to study protein-ligand interactions, a protein structure of interest can be collected from database if 3D crystal structure is known or can be built using template based homology modeling facility. The protein analysis facility of BioPredicta helps to check/repair geometry of protein structure and visualization of various protein cavities before undertaking any protein-ligand interaction study. The molecular docking facility of BioPredicta helps in understanding of mode of binding of ligands to their receptors for successful design of more efficient drugs.

click on image to enlarge MEP mapped on Channel of retinoic acid receptor beta

Advantages Allows the biomolecule handling facilities. Starting from simple visualization as well as editing of protein, this module allows more complex modeling activities like generation of homology model of protein, model validation analysis and molecular docking studies. Allows analysis of protein cavities in terms of shape and electrostatic as well as hydrophobic properties, which further will provide clues for optimization of ligand design. Features Homology Modeling Homology modeling feature of BioPredicta allows execution of the BLAST program for the protein sequence to be modeled to get the template sequence for modeling. This allows selection of template protein for building homology model. This also enables both manual and automated homology modeling from the selected template. Protein Analysis The protein analysis feature of Biopredicta allows: Performing protein local geometry check Identification of residues crossing in protein model Visualization of Ramachandran plot Cavity identification Channel identification Ligand interaction visualizer Molecular Docking The Molecular Docking feature allows rapid identification of the binding mode of ligands to their receptors. This could be done using systematic methods (Grid) or stochastic method (genetic algorithm). Various scoring functions like PLP score, XCscore and Steric + Electrostatic are available for evaluation of the docked poses.

Homology Modeling

Molecular biology techniques have enabled sequencing of number of proteins, but obtaining their three dimensional experimentally resolved structure is still not feasible for all proteins. Thus, alternative strategies are being applied to develop models of proteins. Among these, homology modeling is one of the methods being used most widely. Proteins are modeled using the experimentally resolved structure of the closest homologue, selected based on the percentage identity and similarity of the alignment. Modeling proteins using the closest homologue helps to unveil the structural features of such proteins and the nature of interactions with their ligand, thus enabling structure based drug design.

click on image to enlarge 1QKM superimposed on model of Estrogen receptor alpha shown in ribbon structure

click on image to enlarge Sequence alignment of Estrogen receptor alpha with 1QKM

Advantages Allows automated homology modeling from the selected template. In addition, the user defined template and alignment can also be used for automated homology modeling. Allows modifying the alignment generated by MDS automated homology modeling tool and using it for generating the model. Supports manual modeling by allowing the mutation, insertion, deletion and excision. You can insert loop of your choice based on the RMSD and similarity of the various hits obtained by VLifeMDS from its database.

Features Automated Homology Modeling The BLAST alignment generated is used by the homology modeling option of the VLifeMDS BioPredicta to automatically generate the homology model of the target protein from the crystal structure of the template protein selected. Manual Homology Modeling VLifeMDS BioPredicta allows manual modeling of the protein structure. Manual mode allows mutation, excision, deletion and insertion of residues. Allows the manual insertion of the loop by selecting the start and the end anchor where the loop has to be inserted. You can choose the loop to be inserted based on the RMSD and similarity of the loop from among the various results obtained by VLifeMDS from its database. Blast The Blast feature executes the BLAST utility for protein sequence to be modeled to get the template sequence for modeling. By default the 1st hit is chosen as template for modeling, however, it allows you to select the template from among the list of the results produced based on the percentage similarity and identity of the BLAST alignment. The Edit option allows you to manually modify the BLAST alignment produced and use that alignment for protein modeling.

Protein Analysis

After obtaining three-dimensional structure of a protein either through X-ray crystallography or molecular modeling, understanding essential features of protein are necessary. Protein Analysis module allows you to distribute the secondary structure elements, distribute the Phi-Psi angles of residues in Ramachandran plot, identification and visualization of cavities and channels in the protein. The Ramachandran plot helps in identifying quality of generated homology model of protein. The visualization of protein cavities helps in their comparison across proteins in terms of shape and properties. This further helps in placement of ligand in the cavity.

click on image to enlarge Ramchandran plot of Estrogen receptor alpha model depicting Phi-Psi values

click on image to enlarge Electrostatic potential mapped on the cavity surface of retinoic acid receptor beta1. Blue color region indicates negative electrostatic potential while red color region depicts positive electrostatic potential

Advantages The depiction of protein cavities in terms of shape and ability to texture the cavity surface with molecular properties provide in depth understanding of cavities. The cavity shape enables choice of appropriate ligand and its conformation that is likely to fit in the cavity. The electrostatic properties mapping on cavity and channel surface allows identification of regions of charge localization that can guide ligand placement as well as comparison of cavities and channels. Identification and repair of such bad contacts and regions of residue crosses, which may appear in the model, can be achieved via Biopredicta.

Features Cavity Identification Biopredicta identifies all the cavities present in the protein and ranks them based on their size. You can get the volume and surface area information of each cavity. The residues that are in the neighborhood of cavity are identified and displayed. The cavity shape is shown as an isosurface and Biopredicta allows mapping of electrostatic and hydrophobicity properties over the cavity surface. Channel Identification Biopredicta can identify and visualize of channels in terms of their Lee-Richard's surface. This visualization allows you to identify regions that are exposed to the exterior. The channel surface can also be mapped using electrostatic potential and hydrophobicity. Ramachandran Plot Ramachandran plot allows display of distribution of residues in the protein in terms of their Phi-Psi angles. The regions in the plot helps in identifying residues that are part of core region, allowed region, generously allowed region and disallowed regions of the Ramachandran plot. The number of residues in these regions will help determining quality of homology model. It further helps in determining secondary structure composition of the protein in terms of alpha helix, beta sheet contents. Geometry Check Biopredicta allows you to compare bond lengths, angles and torsions with some known standard values. A detailed report with geometrical parameters that deviate from standard values is provided. Crossing Residues Check Biopredicta allows you to identify residues in the model that cross each other during model generation process. Identification of such events is highly challenging task for any modeler and requires significant time. Biopredicta not only detects the residue crossing regions but also repairs these problems in automated fashion. This relieves extra strain in the generated models. Interactions Allows detailed investigation of ligand-receptor interactions. The following interactions are displayed: hydrogen bonds, charge interactions, hydrophobic interactions and pi-stacking.

Protein Handling

VLifeMDS Protein Handling allows handling of Proteins either from existing databases such as the downloaded protein databases in .pdb format or from in-house protein database. Proteins need to be visualized and manipulated for their various molecular properties in a manner similar to small molecules. VLifeMDS Protein Handling facilitates reading, visualization, editing and superimpositions of protein molecules. More importantly, protein-ligand interaction sites can be accurately identified.

click on image to enlarge 1QKM superimposed on model Estrogen receptor alpha viewing backbone

Advantages Enables quick and easy handling of multiple files. Facilities in Protein editing such as mutations, insertion, excision are handled in a simple manner and are integral part of homology modeling tool. The customizable graphic rendition facility of this feature for the Proteins is a useful tool for visualization and publication purposes. The highly intuitive Protein editor allows focusing on regions of interest in protein like active site and its residues. Features Multiple Protein renditions View the Protein in various renditions such as ribbon, tube, strip and C-a trace. These views are essential to determine the secondary compositions of the proteins, for example: alpha-helix, beta-sheet, coils, loops, turns and so on. The various renditions are useful in analysis of protein structures individually and in comparison to other protein structures/models. The renditions can be modified for color, style and size for publication and presentation purposes. Edit Proteins Edit Proteins through residue mutations, insertions, deletions, extractions, excisions and joins. This utility plays a major role in homology modeling of a protein whose crystal structure is unknown. Coloring / Labeling / Re-numbering of residues Alternatively edit Proteins by coloring and labeling of selected residues of the protein, renumbering the residues in the protein, hiding selected residues or sidechains in the protein, enabling terminal capping of residues and allowing addition of residues to either the C or N terminals of the protein. These tools too are used in homology modeling of query proteins. Inter and Intra-molecule distances View inter and intramolecular atomic distances and angles, either between the protein and ligand or within the Protein itself. Ligand extraction from the complex Extract the ligand from the protein, especially from *.pdb files where co-crystals of ligand and protein (receptor) are available.

Molecular Docking

Molecular Docking is a computational method to find out binding modes of ligands to their receptors rapidly. Molecular interactions play the key role in all biological reactions. Most of the biological reactions get triggered by binding of a small molecular ligand to their receptor, which is usually a protein. Even most of the drugs exert their pharmacological reactions depend only upon their successful binding to their receptor's active site inside the body thus either mimicking or mitigating the effect of natural ligand's binding to the receptor. Hence the understanding of mode of binding of ligands to their receptors will be crucial in successful design of more efficient drugs. Experimental methods to identify these binding modes are more expensive and time consuming.

click on image to enlarge Docked pose of Dexamethasone in Estrogen receptor alpha

click on image to enlarge Interactions of Dienestrol with Estrogen receptor alpha by GRIP Docking

Advantages Docking tool in Biopredicta module of VLifeMDS allows user to rapidly find the binding mode of ligands to their receptors and their interactions. Batch docking of ligands is also possible with this tool, which helps in ranking ligands based on their binding scores. Thus, it is possible to differentiate the ligands, which can bind with high affinity to the receptors active site from other ligands. These features make VLifeMDS docking an indispensable tool in structure based drug design. The case study comparing various docking methods show that docking in VLifeMDS is better or comparable.